2-hydroxymethyl-delta2-corticoids



United States Patent 3,086,012 Z-HYDROXYMETHYL-A -CORTICOIDS Albert Bowers and James C. Orr, Mexico City, Mexico, assignors, by mesne assignments, to Syntex Corporation, a corporation of Panama N0 Drawing. Filed Sept. 15, 1961, Ser. No. 138,266

27 Claims. (Cl. 260-23955) anti-estrogenic and anti-gonadotrophic activities are represented by the following formulas:

CHzOR "-011 INWRI In the above formulas X represents B-hydroxy or keto; Y represents hydrogen, fluorine or chlorine; Z represents hydrogemfluorine, chlorine or methyl; R and R represent hydrogen or a hydrocarbon carboxylie acyl group of less than 12 carbon atoms; R represents hydrogen, a-methy1,

3,086,012 Patented Apr. 16,, 1963 ,B-methyl, a-hydroxyl or (at-hydrocarbon carboxylic acyloxy of less than 12 carbon atoms and R and R represent hydrogen or the residue of a hydrocarbon radical containing up to 8 carbon atoms of straight, branched, cyclic or mixed aliphatic-cyclic chain, saturated or unsaturated and including aromatic groups. The acyl groups are derived from hydrocarbon carboxylic acids containing less than 12 carbon atoms which may be saturated or unsaturated, of straight, branched, cyclic or cyclic-aliphatic chain, aromatic and may be substituted by functional groups such as hydroxy, alkoxy containing up to 5 carbon atoms, acyloxy containing up to 12 carbon atoms, nitro, amino or halogen. Typical ester groups are the acetate, propionate, enanthate, benzoate, trimethylacetate, t-butylacetate, phenoxyacetate, cyclopentylpropionate, aminoacetate and p-chloropropionate.

The novel compounds of the present invention are prepared by the process illustrated by the following equation:

0 all Home I Y u 5 E In the above formulas X, Y, Z and R have the same meaning previously set forth; and A represents a double bond or a saturated linkage between 0-4 and 0-5. V

In practicing the process just outlined the starting 2- formyl 17,20,20,21-bismethylenedioxy-A -alloprcgnen or 2 formyl 17,20;20,21 bisrnethylenedioxy A pregnadien compound (I) (obtained in accordance with our copending US. patent application Serial No. 138,267 filed of even date) is reduced preferably with sodium borohydride to the corresponding 2-hydroxymethyl-17,20;20,21- bismethylenedioxy derivative (II). Hydrolysis of the 17,20;20,2l-bismethylenedioxy group in an acid medium such as 60% formic acid or acetic acid furnishes the corresponding 2-hydroxymethyl-17,2l-di01-20-o1ie derivative (III).

The primary hydroxyl groups of the heretofore obtained compounds, such as those present in the Z-hydroxymethyl group and in the 2l-position, and/or the secondary hydroxyl groups such as the C-16a-hydroxy1, are conventionally acylated in pyridine with an acylating agent, as for example the anhydride of a hydrocarbon carboxylic acid of the type described hereinbefore, thus affording the corresponding acyloxy derivatives.

The above mentioned compounds with a hydroxyl group at 016m and a hydroxyl group at 0-170: are converted into the :,17oc-CYCliC acetal or 16a,17a-cyclic ketal by reaction with an aldehyde or ketone such as acetone, formtion:

Example I A solution of 1 g. of sodium borohydride in 3 cc. of water was added to an ice-cooled solution of 1 g. of 2 formyl 16m methyl 6a fluoro 17,20;20,21 bismethylenedioxy-M-allopregnen-1l-one in 120 cc. of methanol and the mixture was allowed to stand for 16 hours at room temperature. The excess reagent was decomposed by addition of acetic acid, the solution concentrated to small volume in vacuo and diluted with water. The product was extracted with ethyl acetate, the extract was washed with water, dried and evaporated. The solid residue was purified by crystallization from acetonehexane to give the Z-hydroxymethyl-16a-methyl-6a-fiuoro- 17,20;20,21-bismethylenedioxy-A -allopregnen-1l-one.

Following the above technique, there were treated the starting materials listed below, afiording the corresponding products hereinafter set forth.

Starting compound Product 2-forrnyl-16a-methy1-6a,9a-

difluoro-17,20; 20,21-bismethy1- enedioxy-M-allopregnen-ll-one.

2-formy1-9a-fiu0ro-17,20; 20,21-

bismethylenedioxy-A -alloprcgnen-11fl,16a-di01.

2-iormy1-9a-fiuoro-17,20; 20,21-

bismethylenedioxy-N-allopregnen-lfia-ol-ll-one.

2-formy1-17,20; 20,21-bisrnethylencdioxy-A -allopregnen-llfl-ol.

2-formyl-0a-methy1-17,20; 20,21-

bisinethylenedioxy-A -allopregncn-11fl,16u-dio1.

2-formy1-16Bmethyl-00:904-

difiuoro-17,20; 20,21- bismethylencdioxy-N- pregnadien-llB-ol.

2-iormy1-6a, lfifl-dimethyl- 17,20; 20,21-bismethylenedioxy- A A -preg'nadien-1 1,8-01.

2JormyLGa-chloro-Qa-fluoro-l7,20; 20,21-bismethylencdioxy-A pregnadien-l] 5,1604-(1101.

. one.

2-hydr0xymethy1-6a-chloro-9athem-17,20; 20,21-bismethylenedioxy-A -allopregncn-llfldw- 2-hydroxymethyLGa-chIQrQ-Oamom-17,20; 20,21-bismethylenedioxy-A' -pregnadien- 1lfl,16oz-di01.

Starting compound Product 2-formyl-9a-fluoro-17,20; 20,21.-

bismethylenedioxy-A pregnadien-IIBJBa-diol.

2-formyl-16a-methyl-0a-flu0ro- 17,20; 20,21-bismethyleuedioxy- A pregnadien-U-one.

2-formyl-lea-methyl-fia-fluoro- 17,20; 20,21-bismethy1encdioxy- A -pregnadicn-116-ol.

one.

Z-tOrmyI-IGa-methyI-Ga, 9ozdifluoro-17,20; 20,21-bisrnethylenedioxy-A -pregnadie11-11- one.

2-f0rmyl-16B-methy1-6a,9a-

difluoro-17,20; 20,21-bismethylenedioxy-A -pregnadicn-llone.

2-formyl-6a,16B dirnetl1yl-17,20; 20,21-bismethylenedioxy-A pregnadien-ll-one.

2-forrnyl-6a-methy1-17,20; 20,21-

bismethylenedioxy-N preguadien-11fl,16a-diol.

one. 2-11ydroxymethyl-fia-chloro- 9a-fluoro-17,20; 20,2l-bismethylenedioxy-A -prcgnadien-lfiaol-ll-one. 2-hydroxymethy1-9a-fluoro-17,20; 20,21-bismethylenedioXy-A pregnadien-lfia-ol-ll-oue. 2-hydroxymethy1-17,20; 20,21-

bismethylenedioxy-A pregnndien-llB-ol. 2-hydroxymethyl-fia-methyl- 17,20; 20,21-bismethylenedioxy- A -pregnadien-11B,16a-dio1.

Example II diol-l 1,20-dione.

Following the above procedure there were treated the starting compounds listed below atfording the corresponding products hereinafter set forth:

Starting compound Product Z-hydroxymcthyl-lfia-methyl-fia,

Qa-difiuoro-lZZO; 20,21-bismethylenedioxy-A -allopregncn- 11-one.

2-11ydroxymethyl-lfia-methyl-Gafluoro-9a-chloro-17,20; 20-21-bismethylenedioxy-A -allopregnenll-one.

2-11ydroxymethyl-lfia-methyl-fia,

9a-difiuoro-17,20; 20,21-bismethylenedioxy-N-allopregnen- 1113-01. 2-hydroxymethyl-ltlu-methyl-fiamethylenedioxy-A -allopregnen- 11 3-01. 2-hydroxyrnethyl-1iifi-methyl-fia,

9a-difiuoro-17,20; 20,21-bismethylenedioxy-N-alloprcgncnll-one. 2-hydroxy-methyl-lGB-mcthyl-Ga,

9a,difluoro-17,20; 20 21-bismethylenedroxy-N-izllopregucn- 2-hydroxymethyl-0a 16B,dimethyl- 17,20; 20,21-bismethy1enedi0xy- A -nllopregnen-ll-one.

2-hydroxymethyl-fia-chloro-9amore-17,20; 20,21-bismethylenedioxy-A -allopreg'nen-lfi01-01-11- one.

2-hydroxymethyl-6a-ehloro-9afiuoro-17,20; 20,21-bismcthy1enedioXy-N-allopregnend15,1671- Starting compound Product Starting compound Product 2-hyd ro xymethy1-1 fia-methyl-oafiuoro-Qa-chlotO-HJO; 20,21-bismethylenedmxy-N -pregnadienllfi- Z-hydroxymethyl-ltSB-methyl-Ga,

9u-difluoro-17,20; 20,21-bisinethlylenedioxy-A -pregnadien- 2-hydr0kymethyl-6u,16B-

dimethyl-17,20; 20,21-bismethyllenedioxyA -preg-nadien-llflo 2-hydroxymethyl-Qa-fiuoro-17,20; 20,2l-bismethylenedioxy-A pregnadien-lfia-ol-ll-one. 2-hydroxymethyl-17,20; 20,21-bis- V rnethylenedioxy-A -pregnadien- 20,21-bisrnethylenedioxy-N pregnadien-llfllfia-did.

2-hydroxymethyla-fiuoro-A allopregnene-IMJ7a,21-tri01-11, 20-dione.

2-hydroxyrnethyl-6a-methy1-A allopregnene-11B,16a,17a,21- tetrol-ZO-one.

2-hydroxymethy1-16a-methyl-(ia,

9a-difluoro-A -pregnadiene- 11,9,17a,21-trio1-20-one.

2-l1ydroxymethyl-lfia-methylom fluoro-9al-chloro-A -preg'nadiene- 11 3,17a,21-triol-20-one.

2-hydroxymethyl-Qot-fduoro-A pregnadiene-16a,17a,21-trio1- 11,20-dione.

Example III A mixture of 1 g. of 2-hydroxyrnethy1-1Ga-methyI-Gu- 'fiuoro-A allopregnen-170:,21-diol 11,20-dione, 4 cc. of pyridine and 2. cc. ofacetic an-hydride was kept at room temperature overnight, poured into ice water, the formed precipitate was filtered off, washed with water and dried. Crystallization from acetone hexane gave Z-acetoxymeth- 'yl-l 6a-methyl-6a-fiuoro A allopregnen 17a,21 diol- 11,20-dione-2l-acetate.

Following the above technique were treated the starting compounds hereinafter listed, furnishing the products indicated below.

Starting compound Product 2-hydroxymethyl-1Ga-methyl- 17a,21-dio1-11,20-dione-21-acetatee 2-hydroxymethyl-lGfi-methyI-Gu,

Qa-difluoro-A -allopregnene-17a, 21-diol-11,20-dione.

2-hydroxymethyl-fia-methyl-A allopreg'nene-11B,16a,17a,21- tetro1-20-0ne.

2-hydroxymethyl-ilu-fluoro-A pregnadiene-l6a,17a,21-triol-11, 20-dione.

2-hydroxymethyl-A -pregnadiene- 11B,17a,2l-triol-20-0ne.

2-hydroxymethyl-fia-methyl-A ggegnadiene-11B,16a,17a,21-tetro1- -one.

Following the above described procedure but substituting acetic anhydride by propionic anhydride, caproic anhydride and cyclopentylpropionic anhydride there were obtained the corresponding propionates, caproates and cyclopentylpropionates of the hereinbefore listed starting compounds.

Example IV To cc. of acetone containing 1 g. of Z-hydroxymethyl 6m chloro 9oz fluoro A allopregn'ene 16a,17a,21-tri0l-11,20-dione, prepared in Example II,

were added 30 drops of 70% perchloric acid. After one hour at room temperature,'30 drops of pyridine were added and the resulting solution was evaporated to drylisted Starting product Final product Th e acetonlde of 2-hydroxymethyl- (la-ehloro-Qor-fluoro-A -allopregnene llfi,16a17a,21-tetr0l-20-0ne.

The acetonide t Z-hydroxyrnethyl- Qa-fluoro-d allopregnene-l15, 16a,l7u,21-tetrol-20-one.

The acetonide 0t 2-hydroxymethyl- 9a-fluoro-A -allopregnenc-l6a, 17a,21-triol-11,20-dione.

The acetonide of Zhydroxyrnethyl- 9a-tluoroA -pregnadiene-llfl, 16a,17a,21-tetro1-20-one.

one.

The acetonlde of Q-hydroxymethyltia-chloro-Qa-fiuoro-A -pregn adiene-lGa,17a,21-trlol-11,20 dione.

The aeetonide of 2-hydroxy methylallopregnene-llflJGa,1701,21- 6a-methyl-A -allopregnene-1118, tetrol-20-one. 16a,17a,21-tetrol-20-one. 2-hydroxyn1ethyl-6m-methyl-A lhe aeetonlde of 2-hydroxymethylpregnadiene-IIBJBa,1701,21- fia-methyl-A -pregnadiene-11fl, tetrol-20-one. 16a,l7a,21-tetrol-20-one.

Example V By following the procedure described in Example IV except that acetone was substituted by benzaldehyde, paraformaldehyde and cyclohex'anone, there were obtained respectively the corresponding 16a,l7a-benzylidenedioxy, l6a,l7a-methylenedioxy and 16a,17a-cyclohexanone ketal derivatives of the starting compounds of Example IV.

Example VI The final products described in Examples IV and V were converted into the corresponding C-2, C-21-diacetates; C-2, C21dipropionates; 0-2, C-21-dicaproates and C2, C-21-di(cyclopentylpropionates) in accordance with the methods described in Example III.

We claim:

1. A compound of the following formula:

CHzOR m momol wherein R and R are selected from the group consisting 'of hydrogen and a hydrocarbon carboxylic acyl group of less than 12 carbon atoms; R is a member of the group consisting of hydrogen, a-methyl, fl-methyl, a-hydroxyl and a OL-EICYIOXY group derived from a hydrocarbon carboxylic acid of less than 12 carbon atoms; X is selected from the group consisting of B-hydroxyl and keto; Y is a member of the group consisting of hydrogen, fluorine and chlorine and Z is selected from the group consisting of hydrogen, fluorine, chlorine and methyl.

2. 2 hydroxymethyl 16a methyl 6a fluoro A all-opregnen-17a,21-diol-11,20-dione.

3. 2 hydroxymethyl 16a methyl 6a,9a difiuoro A' -allop'regnen-l7a,21-diol-11,20-dione.

4. 2 hydroxymethyl 16a methyl 6oz fluoro 9a chloro-M-allopregnen-17,2l-dioll 1,20-dione.

5. 2 hydroxymethyl 16oz methyl 601,91: difiuoro A -allopregnen-1 1,8, 17a,21-tZ'lOl-20-0116.

6. 2 hydroxymet-hyl 16a methyl 6a fluoro 9m chloro-A al-l-opregnen-1 1/3,17a,21-triol-20-one.

7. 2 hydroxymethyl 16B methyl 604,90: difiuoro d -allopregnen-l 1B,17a,21-triol-20-one.

8. 2 hydroxymethyl 16a methyl 60:,9a difluoro n -allopregnen-17a,21-dio1-11,20-dione.

9. 2 hydtroxymethyl 60:,165 dimethyl A allopregnen-17a,21-diol-l1,20-dione.

10. 2 hydroxymcthyl 6m,16}3 dimethyl e. A allopregnen-l 118,17a,21 triol-20-onc.

l1. 2 hydroxymethyl 6a. chloro 9a fluoro A allopregnen-16a,17u,2l-triol-l1,20-dione.

12. 2 hydroxymethyl 6oz chloro 9a fluoro A allopregnen-l 1B,16a,17a,21-tetrol-20-one.

13. A compound of the following formula:

CHzOR wherein R and R are selectedfrom the group consisting of hydrogen and a hydrocarbon carboxylio acyl group of less than.12 carbon atoms; R is a member of the group consisting of hydrogen, a-methyl, p-methyl, a-hydroxyl and an ot-acyloxy group derived from a hydrocarbon carboxylic acid of less than 12 carbon atoms, X is selected from the group consisting of fl-hydroxyl and keto; Y is a member of the group consisting of hydrogen, fluorine and chlorine and Z is selected from the group consisting of hydrogen, fluorine, chlorine and methyl.

14. 2 hydroxymethyl 16a, methyl 6a fluoro-A pregnadien-17a,21-diol-11,20-dione.

l5. 2 hydroxymethyl 16oz methyl 6a,9u difluoro- A -pregnadien-17u,21-diol-11,20-dione.

16. 2 hydroxymethyl 16a methyl 6oz fluoro- 9rx chloro A pregnadien 17a,21 diol 11,20- dione.

17. 2 hydroxymethyl 16a methyl 6a,9a difiuor0A -pregnadien-1lB,17u,2l-triol-20-one.

18. 2 hydroxymethyl 16cc methyl 60c fiuoro-9achloro-d -pregnadien-1 1fl,17a,21-triol-20-one.

19. 2 hydroxymethyl 161i methyl 6a,9a di- 20. 2 hydroxymethyl 165 methyl 60:,9ot-difltl0f0- A -pregnadien-17a,21-diol-11,2O-dione.

21. 2 hydroxymethyl 60:,165 dimethyl A -pregnadien-17a,21-diol-11,20-dione.

22. 2 hydroxymethyl 60,16f3 dimethyl A pregnadien-l1fl,17a,2l-tri0l-20-one.

23. 2 hydroxymethyl 6a chloro 9a fluoro-A pregnadien-16a,17a-21-triol-1 1,20-dione.

24. 2 hydroxymethyl 6a chloro 9oz fluoro-A pregnadien-l1,8,16a,17a,2l-tetrol-20-one.

9 25. A compound of the following formula:

OHflOR it) 27. A compound of the following formula:

GHrOR wherein X is selected from the group consisting of 5- hydroxyl and keto; Y is a member of the group consisting of hydrogen, fluorine and chlorine and Z is selected from the group consisting of hydrogen, fluorine, chlorine and methyl; R and R are selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl group of less than 12 carbon atoms; and R and R are each selected from the group consisting of hydrogen and a hydrocarbon radical containing up to 8 carbon atoms.

No references cited. 

1. A COMPOUND OF THE FOLLOWING FORMULA:
 27. A COMPOUND OF THE FOLLOWING FORMULA: 2-(R2-O-CH2-),6-Z,9-Y,11-(X=),16,17-(-O-C(-R3)(-R4)-O-), 21-(R-O-)-PREGN-2-EN-20-ONE 